key: cord-0800104-p6q2ryfa
authors: Boelig, Rupsa C.; Aagaard, Kjersti M.; Debbink, Michelle L.P.; Shamshirsaz, Alireza A.
title: SMFM Special Statement: COVID-19 Research in Pregnancy: Progress and Potential
date: 2021-09-03
journal: Am J Obstet Gynecol
DOI: 10.1016/j.ajog.2021.08.039
sha: 233a9466ed37210a5d1d0ab136a139f0608e5abe
doc_id: 800104
cord_uid: p6q2ryfa

The COVID-19 global pandemic has broad implications for obstetrical care and perinatal outcomes. As we approach the 2-year mark into an unprecedented international pandemic, this review presents the progress and opportunities for research related to COVID-19 and pregnancy. Research is the basis for evidence-based clinical guidelines, and we aim to provide the structure and guidance for framing COVID-19-related obstetrical research. This structure will pertain not only to this pandemic but future ones as well.

Intimate partner violence (IPV) increases in frequency during pregnancy and is associated with adverse perinatal outcomes. 7 The complex layers of instability during the pandemic have contributed to an increase in IPV across the globe. 8 Stay-at-home mandates in many countries were associated with increased calls to authorities for assistance with IPV. 9 In other regions, reports of IPV fell, which some have attributed to the inability of those experiencing violence to discreetly and safely connect with services. 8 Economic independence is a key element in separating from an abusive partner, which is more difficult to achieve during a pandemic.

Like others who worked during the COVID-19 pandemic, pregnant individuals have experienced various changes in their work environments. Stressful working conditions (whether physical or emotional) have been implicated in adverse perinatal outcomes. 10 Work environment changes related to COVID-19 may have both positive and negative impacts on work stress. One large survey of workplace changes related to COVID-19 and employee stress conducted at a large academic medical center revealed that workplace stress was higher than anticipated for most individuals. 11 However, some of this stress was mitigated by flexible work-from-home policies and transparent scheduling.

From a community perspective, COVID-19 hardships such as job loss, the proportion of COVID-19 infections and deaths, and business and school closures are not distributed evenly among neighborhoods or communities. Due to structural inequities, pandemic impacts are concentrated in marginalized communities, which may, in turn, affect pregnancy outcomes. Economic and racial segregation is associated with low birth weight, small-for-gestational-age neonates, and preterm birth, 12, 13 and these associations are most often attributed to chronic stress. These relationships may be further heightened due to the concentration of COVID-19 hardships in these same communities. For instance, in middle-and working-class Black communities, men are dying of COVID-19 at younger ages compared with White individuals. 14, 15 The disproportionate loss of wage-earning middle-aged Black individuals exacerbates the economic impact of the pandemic in these communities and may strain neighborhood recovery efforts.

Environmental exposures J o u r n a l P r e -p r o o f this arena include developing multi-institutional, multidisciplinary teams to accomplish large observational studies of the adverse pregnancy outcomes we hope to measure. As mentioned, GRAVID will accomplish this objective for a subset of patients across the country and will be large enough to measure maternal morbidity in addition to pregnancy outcomes such as preterm birth, stillbirth, and low birth weight. Perinatal research in this area would benefit greatly from partnerships with experts in other disciplines, including mental health experts, economists, sociologists, and geographers, to best represent and analyze complex macrosocial data.

Another opportunity for improved understanding is through observational studies that oversample smaller at-risk populations. For example, Native and Indigenous peoples, especially those living on reservations in the United States, have been particularly devastated by the COVID-19 pandemic. 22 Structural inequity and broken treaty obligations have led to poor healthcare access, limited water and internet access, and transportation difficulties on Native reservation lands that exacerbate COVID-19 spread and worsen outcomes. Despite these difficulties, tribal leaders have developed rapid and resourceful responses based on Native knowledge and community that may also serve as learning opportunities for other systems. 23 However, large data gaps remain that hamper efforts to understand the scope of the problem or disseminate knowledge. Developing partnerships with Tribal Epidemiology Centers and sovereign Native nations to highlight tribal knowledge (while preserving data sovereignty) around pregnancy and perinatal consequences of the pandemic among pregnant Native and Indigenous individuals would prove beneficial.

Current knowledge and ongoing research Worldwide, changes of varying intensity occurred in healthcare delivery and access associated with shelter-in-place orders, including hospital capacity limitations and changes in healthcare delivery to limit disease transmission. Prenatal care, labor, and delivery occur over a relatively short period of weeks; therefore, changes in healthcare access may have a stronger impact during this compressed period.

Diminished and altered access to healthcare is impacted by the macrosocial forces delineated in the prior section. An early modeling study funded by the Gates Foundation suggested that both maternal and child mortality were expected to increase in low-and middle-income countries with COVID-19-related worsening of access to healthcare and malnutrition. 24 One prospective study in Nepal found a 50% decrease in "in-hospital births," and the authors surmise that pregnant individuals stopped presenting for care because of a fear of disease transmission in hospitals and lack of public transportation due to lockdown. 25 They also found an increase in perinatal mortality and preterm birth during that country's COVID-19 pandemic lockdown. 25 One study in the United Kingdom also identified a higher rate of stillbirth during the pandemic period not associated with maternal SARS-CoV-2 infection compared with a historical cohort, 26 which the authors speculate is associated with reduced prenatal care-seeking. 27 In contrast, other observational studies across Europe and the United States have identified a decrease in the preterm birth rate during the COVID-19 pandemic. 28, 29 These conflicting findings highlight the need to assess not only access to healthcare but to include the macrosocial impacts on preterm birth and perinatal mortality highlighted in the prior section.

As hospital systems struggled to respond to varying access challenges while diminishing disease transmission, alternative prenatal care models expanded rapidly, including telehealth, home blood pressure monitoring, and changes in antenatal visit timing. 30 Randomized trials of interspersing in-person antenatal visits with telehealth or remote services show equal rates of safety and improved or similar patient satisfaction for low-risk prenatal care compared with standard care. 31-33 However, the safety, efficacy, and patient tolerance of reduced-visit schedules and home monitoring using blood pressure cuffs and fetal Doppler monitors on a large scale are unknown.

Because alterations in the availability or delivery method of prenatal care may have benefits or risks both during and after the pandemic, research is necessary to tease out the positive and negative effects of healthcare delivery changes, including 1) the differential impact of healthcare availability vs. macrosocial J o u r n a l P r e -p r o o f changes (employment, environment, and psychosocial stress); 2) the equitable distribution of access to "COVID-safe" remote perinatal care access; 3) whether flexible and remote prenatal care options assuage psychosocial stress associated with the pandemic; and 4) the utility of interspersing remote monitoring and virtual prenatal care more widely even after the conclusion of the pandemic to increase prenatal care access more broadly.

Additionally, there is a need to survey access to and utilization of in-person and remote healthcare resources throughout the country in both urban and rural areas. Evaluation of payer databases (such as private health insurance, Kaiser, state Medicaid) linked to birth outcomes provides an avenue to investigate differential utilization of telehealth vs in-person antenatal care visits and relationship to patient demographics and perinatal outcomes. Concerns have been raised about inequitable access to telehealth care for patients without internet access, including rural, financially disadvantaged, homeless, and migrant patient populations. 34 A recent retrospective study of over 1000 rural US counties found that loss of hospital-based obstetric care was associated with increases in both preterm births and out-of-hospital births. 35 Even prior to this pandemic, telemedicine has been studied as a means to improve healthcare access in rural areas. However, despite the potential benefits of telehealth, barriers continue to exist, including the cost of implementing such systems and technical issues, such as broadband access. 36, 37 Barriers to telehealth access and utilization are compounded by a general decline in access to obstetric services in rural counties over the past decade 38 and highlight the importance of studying the impact of pandemic-related alternative healthcare models not just at a national level but at regional levels, in rural communities, migrant populations, and other vulnerable groups.

J o u r n a l P r e -p r o o f Emerging novel strains of influenza and coronaviruses that cause severe respiratory disease 39-41 typically disproportionately affect pregnant people, in part due to the adaptive immunology and cardiopulmonary physiology of pregnancy. [42] [43] [44] [45] [46] [47] Of note, the risks of morbidity with severe lower respiratory infections are not limited to maternal outcomes. Neonatal morbidity, including increased risks of preterm birth, fetal demise, and delivery of low-birth-weight infants, is associated with nearly all maternal severe lower respiratory viral infections. [39] [40] [41] [42] 47 Evaluating morbidity and mortality in pregnant vs nonpregnant adults is difficult due to inherent biases in reporting and publication. Data on whether pregnant women are more or less susceptible to severe COVID-19 disease remain mixed. 48-51 COVID-19 disease in pregnancy is associated with an increased risk of severe maternal and neonatal morbidity, including increased rates of preeclampsia, preterm birth, cesarean delivery, and low-birth-weight infants. 46, [52] [53] [54] [55] [56] [57] As the pandemic progresses, further data on perinatal complications related to the trimester of infection should be evaluated. As we reach the midpoint of 2021, it is incumbent to understand horizontal (person to person) and vertical (mother to child) transmissibility and disease severity with emerging SARS-CoV-2 variants and variant strains during pregnancy and the postpartum interval, especially among those who are not vaccinated.

The COVID-19 pandemic has laid bare the impact of structural and systemic racism on health outcomes.

As in the nonpregnant population, COVID-19 has differentially affected Black and Hispanic pregnant individuals. 58, 59 Data from the MFMU Network GRAVID study demonstrate that although disease severity in pregnant individuals may not differ across racial groups, racial and ethnic minority groups are overrepresented among pregnant individuals who have tested positive for COVID-19. 60 This observation suggests that structural differences in access to healthcare resources and opportunities may drive increased infection rates among minority populations, leading to an increased burden of COVID-19 in these communities. Other socioeconomic factors contributing to an increased risk of perinatal COVID-19 disease were elucidated by a study conducted in New York City and include living with a higher number J o u r n a l P r e -p r o o f of individuals in the household, higher community unemployment rates, and living in larger residential units. 61 The specter of implicit bias in healthcare delivery may also increase the likelihood of disparities in mortality or severe outcomes from COVID-19 infection. In addition, Black, Hispanic, and other individuals of color have disproportionately higher rates of hypertension, asthma, diabetes, obesity, and other chronic diseases at younger ages, which many attribute to the long-term health impacts of structural racism. 3, 62 These increased rates of comorbidity are associated with increased COVID-19 severity and associated mortality at younger ages among Black and Hispanic individuals compared with Whites. 14, 63 Mechanisms driving unexpectedly severe disease among healthier individuals are not yet elucidated; however, there is no biologically plausible reason why individuals of Black, Hispanic, or other minority racial or ethnic identities would develop more severe disease based solely on their race or ethnicity, as these are socially determined categories. A small number of studies in pregnant and nonpregnant individuals affected by the pandemic have highlighted the social construction of racial disparities, 61, 64 but further work to understand and dismantle the impacts of racism is needed.

The NICHD is participating in the National Institute of Health's (NIH) Rapid Acceleration of Diagnostics (RADx-UP) program, which will employ a perinatal health lens to this ongoing work. 65 The RADx-UP program seeks to understand factors associated with disproportionate rates in COVID-19 morbidity and mortality and reduce disparities for underserved and vulnerable populations that are disproportionately affected by, have the highest infection rates of, and are most at risk for complications or poor outcomes from COVID-19. In addition, the NICHD GRAVID study will collect information about the perinatal outcomes of pregnant women infected with SARS-CoV-2. 66 Internationally, the NICHD-funded Global Network is examining maternal and neonatal outcomes in women with and without perinatal SARS-CoV-2 infection across multiple sites in South Asia and Africa. 67 Each of these ongoing studies will contribute to our understanding of COVID-19 in pregnancy, both from the standpoint of individual response to disease and the social determinants of COVID-19 outcomes in pregnancy.

Although initial reports from China suggested a possible protective effect of pregnancy against COVID-19 morbidity and mortality, more recently published manuscripts from other continents report equally or more severe disease and mortality in pregnant individuals compared with nonpregnant individuals, 54, 55, [68] [69] [70] as has been reported in past pandemics. Although the reason for the differences between initial reports from China and subsequent reports from elsewhere in the world is currently unknown, several possible explanations have been proposed. First, it is anticipated that during any pandemic, initial reporting via case series will be incomplete and subject to nonrandom selection bias. Assessment of epidemiologic characteristics, including case-fatality ratios during a pandemic, may be affected by right (Type I) censoring and ascertainment bias. Right censoring reflects poor outcomes that may occur outside the time to reporting interval and tends to underestimate morbidity or mortality; in contrast, ascertainment bias of poor outcomes tends to overestimate mortality. Mizumoto and colleagues report that when an emerging pandemic overwhelms a healthcare system, underestimation of true disease burden and ascertainment bias occur. 71 In addition, large upper limit confidence intervals will always accompany small case series with zero mortality, leading to a false reassurance regarding the risk of death in early reporting. Because of this censoring bias (which is exacerbated in pregnancy and postpartum periods due to their inherently prolonged intervals), future research in subsequent pandemics should not quantify risk or estimate mortality rates based on case reports or small series.

Addressing this issue will involve developing adequate global reporting mechanisms to rapidly collect, of pregnancy-specific data could be easily rectified given that therapies under study, such as anticoagulants aspirin, heparin or enoxaparin, anti-inflammatory drugs, and immunomodulators, are already used frequently in pregnancy and have a reassuring safety profile. 74, 75 Multiple therapeutic areas should be studied specifically in pregnancy. The ideal regimen for anticoagulation in the setting of COVID-19 remains controversial. 76 This issue has not been studied in J o u r n a l P r e -p r o o f pregnancy, 77 a critical oversight given that the risks for thrombosis are inherently higher during pregnancy and the postpartum period. Furthermore, placental macro-or microthrombosis may be associated with preeclampsia and fetal growth restriction, which are additional outcomes that should be considered when studying the indications for and timing of anticoagulation in the setting of COVID-19 in pregnancy.

Another key area of interest is the management of the critically ill pregnant patient. Maternal Finally, the rapidly emerging SARS-CoV-2 vaccines must be addressed. Vaccine trials in pregnancy have begun (NCT04765384, NCT04754594), and initial vaccination reports in pregnancy are emerging. [80] [81] [82] [83] [84] The ethics of a placebo-controlled vaccine trial in pregnancy when vaccines are available widely, albeit still under an emergency authorization, for a condition that has pregnancy-specific morbidity and mortality is questionable. However, pregnancy-specific studies are key, as shown by studies of other vaccines in pregnancy (influenza, pertussis) that have yielded information about the timing of administration to optimize both maternal and neonatal immunity. 85 This approach allows rapidly emerging, novel, life-saving therapies to be approved with data available on pregnancy. For therapies already approved in nonpregnant adults, focused studies in pregnancy are also important; however, single-arm or dual active-arm studies are preferable to avoid withholding potentially life-saving therapy. Finally, the U.S. Food and Drug Administration (FDA) has recognized the harm of excluding pregnant patients from research, acknowledging that "the frequent lack of information based on clinical data often leaves the healthcare provider and patient reluctant to treat the underlying condition, which in some cases may result in more harm to the woman and the fetus than if she had been treated."

In addition to declaring that "development of accessible treatment options for the pregnant population is a significant public health issue, " 87 the FDA also provides basic guidance for the inclusion of pregnant patients in research.

One reason that the severity of COVID-19 disease was initially underestimated in pregnancy is likely related to challenges in classifying the distinct pathophysiology of the disease. The general effects of symptomatic SARS-CoV-2 infection (which functionally defines COVID-19 disease) is now appreciated to fall into three key categories: respiratory, 88 cardiopulmonary, 89 and systemic inflammation with or without sepsis or vasculitis (including the so-called "cytokine storm"). 90, 91 Maternal immune response

Although it is frequently stated that pregnant women are "immunosuppressed," such assumptions are incorrect. 43 Rather, human pregnancy represents highly adaptive immunity, including competency of Bcell-mediated humoral, innate, and T-cell-mediated immune responses that allow the pregnant person to become tolerant to the fetus yet remain immunocompetent to ward off pathogens. 43 There are emerging studies on both maternal immune response and vertical transmission of immunity. [92] [93] [94] [95] The systemic inflammatory response identified with SARS-CoV-2, a profound cytokine storm leading to sepsis or a vasculitis-like response, has now been well-documented. 90, 91 In general, the most consistent pattern of this cytokine storm involves upregulation of three general classes of cytokines and chemokines: J o u r n a l P r e -p r o o f bears 80% to 85% nucleotide homology to SARS-CoV-1. 103 Although both SARS-CoV-1 and CoV-2 bind ACE2 via the viral surface spike glycoprotein (S protein, 76% protein identity), potential differences in the role of specific serine and cysteine proteases in cleavage of the S protein in priming for enhanced cell entry may exist between these two viruses. [103] [104] [105] When considering the potential for vertical transmission, both the placenta and stool/meconium may be of importance, as a less-lethal common Coronaviridae (229E) genus is known to be transplacentally transmitted. However, whether it uses the same or different cell entry receptors as SARS-CoV-2 (eg, ACE2) is unknown. 106, 107 Moreover, although ACE2 mRNA is more highly expressed in human placental syncytiotrophoblasts early in gestation, and ACE protein localizes to fetal endothelium, the placental expression of host proteases (such as TMPRSS2 and others) necessary for cleavage of the S protein and receptor priming is unknown and has generally only been described in lung and airway cells or their progenitors. 108 As a result, whether the necessary and sufficient host molecular machinery to enable efficient transplacental vertical transmission and subsequent fetal infection is present or absent in the second-or third-trimester human placenta remains controversial. 109, 110 However, most high-quality studies consistently report placental detection of SARS-CoV-2 virus, which may or may not portend clinically meaningful fetal infections detectable in the liveborn neonate. 100, 101, [110] [111] [112] [113] [114] [115] [116] [117] [118] [119] [120] [121] [122] Regarding fecal-oral transmission, SARS-CoV-2 RNA has been found in stool samples of people infected with the virus, some of whom tested negative from respiratory samples. Additionally, immunofluorescence visualization of biopsy specimens is consistent with viral uptake in the glandular cells of the gastric, duodenal, and rectal epithelia. [123] [124] [125] These findings raise concern for the possibility of The NICHD is also participating in the RADx-UP initiative that aims to identify biomarkers and tools to improve diagnostic strategies for COVID-19 and predict the severity of COVID-19 disease in pregnant people and children.

Another specific area of need in COVID-19 related research is the identification of prognostic markers in pregnancy. Cellular and cytokine studies in COVID-19 have shown rapid induction of antibodyproducing cells and follicular T-helper cells during infection, 126 and SARS CoV-2-specific CD4+ and CD8+ T cells have been identified in convalescent patients. 127 Lymphocytopenia has been observed, 128 especially a reduction in CD4+ and CD8+ T cells, and is predictive of COVID-19 progression. 129 In systemic cytokine responses, studies report high levels of several cytokines, including IL-6 and IL-8, associated with COVID-19, 129, 130 suggesting that proinflammatory mediators contribute to disease severity. Notably, both mild and severe forms of disease result in changes in levels of circulating cytokines and chemokines. 131 To date, the effects of COVID-19 related cytokine responses on pregnancy are unknown, including association with disease severity and latency to delivery. A maternal inflammatory response can lead to a fetal inflammatory response syndrome. Prior research suggests that increased levels of IL-6 are associated J o u r n a l P r e -p r o o f with preterm birth, 132 fetal growth restriction, 133 and fetal inflammatory response syndrome, 134 all of which are associated with adverse short-and long-term neonatal outcomes. These associations highlight the link between cellular/innate immunity and maternal and perinatal (fetal/neonatal) health.

Other biomarkers of interest identified in nonpregnant populations should be studied specifically in pregnancy because many of these markers are altered during pregnancy and labor. Such biomarkers include inflammatory markers such as IL-6, C-reactive protein, erythrocyte sedimentation rate, lactate dehydrogenase; 135, 136 hematologic parameters including platelet count and activity and d-dimer levels; 137 and immunologic markers such as T-cell cytology. 129 Characterization of the COVID-19 disease process 

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